EPR Characterization of Copper(II) Complexes of PAMAM-Py Dendrimers for Biocatalysis in the Absence and Presence of Reducing Agents and a Spin Trap

Polyamidoamine (PAMAM) dendrimers at different generations (from G2 to G6) were functionalized with pyridine (Py) groups at the external surface, and their complexation behavior with Cu­(II) at increasing molar ratios between the ions and the Py groups was analyzed in the absence and presence of reducing agents and a spin trap. These Cu­(II)–dendrimer complexes may be used as antitumor and antiamyloidogenesis drugs, similarly to other Cu­(II)–dendrimer complexes, and as biocatalysts. Indeed, they have revealed to selectively catalyze molecular oxygen reduction to generate reactive oxygen species (ROS). A computer-aided electron paramagnetic resonance (EPR) study of these complexes allowed us to identify different complexes by increasing the Cu­(II)/Py molar ratio for the different generations. Binuclear EPR-silent complexes were formed at the highest generations. The differently complexed Cu­(II) ions showed a different capability to be reduced, starting from the most exposed at the dendrimer surface bearing a stable Cu­(II)–Py₂ coordination. Cu­(II)–G5 showed peculiar structural properties which probably favored its activity as biocatalyst. The spin trap was able to capture hydroxyl radicals, which became clearly EPR visible after all Cu­(II) ions were reduced to Cu­(I). This method may be used as a platform to study interactions of Cu­(II) in nanosized macromolecules for biomedical purposes, mainly in biocatalysis involving redox reactions and formation of ROS

DFT Reinvestigation of DNA Strand Breaks Induced by Electron Attachment

The benchmark study of DFT methods on the activation energies of phosphodiester C3′–O and C5′–O bond ruptures and glycosidic C1′–N bond ruptures induced by electron attachment was performed. While conventional pure and hybrid functionals provide a relatively reasonable description for the C1′–N bond rupture, they significantly underestimate the energy barriers of the C–O bond ruptures. This is because the transition states of the later reactions, which are characterized by an electron distribution delocalized from the nucleobase to sugar–phosphate backbone, suffer from a severe self-interaction error in common DFT methods. CAM-B3LYP, M06-2X, and ωB97XD are the top three methods that emerged from the benchmark study; the mean absolute errors relative to the CCSD­(T) values are 1.7, 1.9, and 2.2 kcal/mol, respectively. The C–O bond cleavages of 3′- and 5′-dXMP^•–, where X represents four nucleobases, were then recalculated at the M06-2X/6-31++G**//M06-2X/6-31+G* level, and it turned out that the C–O bond cleavages do not proceed as easily as previously predicted by the B3LYP calculations. Our calculations revealed that the C–O bonds of purine nucleotides are more susceptible than pyrimidine nucleotides to the electron attachment. The energies of electron attachment to nucleotides were calculated and discussed as well

Theoretical Study of the Protonation of the One-Electron-Reduced Guanine–Cytosine Base Pair by Water

Prototropic equilibria in ionized DNA play an important role in charge transport and radiation damage of DNA and, therefore, continue to attract considerable attention. Although it is well-established that electron attachment will induce an interbase proton transfer from N1 of guanine (G) to N3 of cytosine (C), the question of whether the surrounding water in the major and minor grooves can protonate the one-electron-reduced G:C base pair still remains open. In this work, density functional theory (DFT) calculations were employed to investigate the energetics and mechanism for the protonation of the one-electron-reduced G:C base pair by water. Through the calculations of thermochemical cycles, the protonation free energies were estimated to be in the range of 11.6–14.2 kcal/mol. The calculations for the models of C^•–(H₂O)₈ and G­(−H1)⁻(H₂O)₁₆, which were used to simulate the detailed processes of protonation by water before and after the interbase proton transfer, respectively, revealed that the protonation proceeds through a concerted double proton transfer involving the water molecules in the first and second hydration shells. Comparing the present results with the rates of interbase proton transfer and charge transfer along DNA suggests that protonation on the C^•– moiety is not competitive with interbase proton transfer, but the possibility of protonation on the G­(−H1)⁻ moiety after interbase proton transfer cannot be excluded. Electronic-excited-state calculations were also carried out by the time-dependent DFT approach. This information is valuable for experimental identification in the future

Copper(I) Nitro Complex with an Anionic [HB(3,5-Me₂Pz)₃]⁻ Ligand: A Synthetic Model for the Copper Nitrite Reductase Active Site

The new copper­(I) nitro complex [(Ph₃P)₂N]­[Cu­(HB­(3,5-Me₂Pz)₃)­(NO₂)] (<b>2</b>), containing the anionic hydrotris­(3,5-dimethylpyrazolyl)­borate ligand, was synthesized, and its structural features were probed using X-ray crystallography. Complex <b>2</b> was found to cocrystallize with a water molecule, and X-ray crystallographic analysis showed that the resulting molecule had the structure [(Ph₃P)₂N]­[Cu­(HB­(3,5-Me₂Pz)₃)­(NO₂)]·H₂O (<b>3</b>), containing a water hydrogen bonded to an oxygen of the nitrite moiety. This complex represents the first example in the solid state of an analogue of the nitrous acid intermediate (CuNO₂H). A comparison of the nitrite reduction reactivity of the electron-rich ligand containing the CuNO₂ complex <b>2</b> with that of the known neutral ligand containing the CuNO₂ complex [Cu­(HC­(3,5-Me₂Pz)₃)­(NO₂)] (<b>1</b>) shows that reactivity is significantly influenced by the electron density around the copper and nitrite centers. The detailed mechanisms of nitrite reduction reactions of <b>1</b> and <b>2</b> with acetic acid were explored by using density functional theory calculations. Overall, the results of this effort show that synthetic models, based on neutral HC­(3,5-Me₂Pz)₃ and anionic [HB­(3,5-Me₂Pz)₃]⁻ ligands, mimic the electronic influence of (His)₃ ligands in the environment of the type II copper center of copper nitrite reductases (Cu-NIRs)

Copper(I) Nitro Complex with an Anionic [HB(3,5-Me₂Pz)₃]⁻ Ligand: A Synthetic Model for the Copper Nitrite Reductase Active Site

The new copper­(I) nitro complex [(Ph₃P)₂N]­[Cu­(HB­(3,5-Me₂Pz)₃)­(NO₂)] (<b>2</b>), containing the anionic hydrotris­(3,5-dimethylpyrazolyl)­borate ligand, was synthesized, and its structural features were probed using X-ray crystallography. Complex <b>2</b> was found to cocrystallize with a water molecule, and X-ray crystallographic analysis showed that the resulting molecule had the structure [(Ph₃P)₂N]­[Cu­(HB­(3,5-Me₂Pz)₃)­(NO₂)]·H₂O (<b>3</b>), containing a water hydrogen bonded to an oxygen of the nitrite moiety. This complex represents the first example in the solid state of an analogue of the nitrous acid intermediate (CuNO₂H). A comparison of the nitrite reduction reactivity of the electron-rich ligand containing the CuNO₂ complex <b>2</b> with that of the known neutral ligand containing the CuNO₂ complex [Cu­(HC­(3,5-Me₂Pz)₃)­(NO₂)] (<b>1</b>) shows that reactivity is significantly influenced by the electron density around the copper and nitrite centers. The detailed mechanisms of nitrite reduction reactions of <b>1</b> and <b>2</b> with acetic acid were explored by using density functional theory calculations. Overall, the results of this effort show that synthetic models, based on neutral HC­(3,5-Me₂Pz)₃ and anionic [HB­(3,5-Me₂Pz)₃]⁻ ligands, mimic the electronic influence of (His)₃ ligands in the environment of the type II copper center of copper nitrite reductases (Cu-NIRs)

Dendrimers Terminated with Dichlorotriazine Groups Provide a Route to Compositional Diversity

Triazine dendrimers terminated with either four or eight dichlorotriazines can be prepared in high yields by reacting an amine-terminated dendrimer with cyanuric chloride. These materials exist as white powders and are stable to storage at room temperature. Sequential nucleophilic aromatic substitution with two different amine nucleophiles yields compounds that display the desired compositional diversity. Reaction conditions for the substitution were developed using a model dichlorotriazine with amine nucleophiles at −20, 0, and 25 °C. Selective substitution is favored at lower temperatures and with more nucleophilic amine groups

A Novel Anabolic Agent: A Simvastatin Analogue without HMG-CoA Reductase Inhibitory Activity

For the first time, structural information regarding the role of simvastatin in bone anabolism is described, and a bone-specific statin is introduced. Polyaspartate-conjugated simvastatin was synthesized by solid-phase synthesis with the assistance of microwave irradiation. It displays significant bone targeting and bone formation with less toxicity than simvastatin